1. Field of the Invention
The present invention relates generally to the field of cancer therapy. More particularly, it concerns formulations and methods for the treatment of cancer patients using compositions including specific platinum complexes and/or inhibitors of glutathione (GSH) synthesis or activity, such as L-buthionine-sulfoximine (BSO).
2. Description of Related Art
Cisplatin is one of the most effective and broadly used anticancer drugs. Apoptosis induced by cisplatin is generally considered to be mediated by the formation of covalent DNA adducts, which block replication and transcription. Cisplatin (cis-diamminedichloroplatinum) has been used as a chemotherapeutic agent for many years. Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs. The compounds were effective for treating leukemia and tumors induced in mice. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs.
Platinum-based antitumor agents (e.g., cisplatin and carboplatin) play critical roles in the treatment of several cancers. One of the major limitations to these treatments is relapse in a majority of patients, which fail subsequent treatment with platinum agents due to drug resistant tumor cells. This limitation has resulted in an effort to identify platinum analogs that are effective against resistant tumors. Indeed several such analogs (e.g., oxaliplatin and JM216) have entered clinical trials. However, little or no knowledge of the effective mode of action of these analogs is known. Although reduced drug accumulation, increased intracellular glutathione, and increased DNA adduct repair are usually identified as key mechanisms of resistance for cisplatin, satisfactory explanations for reversal of resistance by analogs have not been provided.
Attempts have been made to increase the effectiveness or sensitize resistant tumor cells to cisplatin or analogs thereof by administering the drug in combination with sulfoximines, for example D,L-buthionine-S,R-sulfoximine (BSO) or other agents. The effects of BSO on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic agents in a human melanoma cell line (RPMI 8322) have been investigated. BSO pretreatment enhanced cytotoxicity of melphalan and nitrogen mustard. A small but significant potentiation by BSO of cisplatin toxicity was also seen (dose modification factor (DMF) of 1.5). The findings supported the hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione.
None of the methods for the treatment of cancer, are entirely satisfactory, thus new and improved methods and compositions for the treatment of cancer are needed.